Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.
- Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington.
- Department of Genetics, Stanford University, Stanford, California.
- Division of Biostatistics, Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
- Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Bioinformatics and Data Science Research Center, Bina Nusantara University, Jakarta, Indonesia.
- Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom.
- Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
- Colorectal Oncogenomics Group, Department of Clinical Pathology, The University of Melbourne, Parkville, Victoria, Australia.
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, Georgia.
- Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain.
- Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
- Division of Gastroenterology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
- Department of Preventive Medicine and USC Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California.
- Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, France.
- Clinical and Translational Epidemiology Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California.
- Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada.
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
- Institute of Cancer Research, Department of Medicine I, Medical University Vienna, Vienna, Austria.
- Nutrition and Metabolism Section, International Agency for Research on Cancer, World Health Organization, Lyon, France.
- Division of Human Genetics, Department of Internal Medicine, The Ohio State University Comprehensive Cancer Center, Columbus, Ohio.
- Department of Radiation Sciences, Oncology Unit, Umeå University, Umeå, Sweden.
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.
- Center for Gastrointestinal Biology and Disease, University of North Carolina, Chapel Hill, North Carolina.
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
- University of Hawaii Cancer Center, Honolulu, Hawaii.
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, California.
- Department of Family Medicine, University of Virginia, Charlottesville, Virginia.
- Oncology Data Analytics Program, Catalan Institute of Oncology-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain.
- Department of Epidemiology, Richard M. Fairbanks School of Public Health, Indianapolis, Indiana.
- Department of Pathology, School of Medicine, Umm Al-Qura'a University, Saudi Arabia.
- Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology (ICO-IDIBELL), Avda Gran Via Barcelona 199-203, 08908L'Hospitalet de Llobregat, Barcelona, Spain.
- Department of Epidemiology, Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts.
- Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah.
- Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, Arizona.
- Slone Epidemiology Center at Boston University, Boston, Massachusetts.
- Department of Population Health Sciences, University of Utah, Salt Lake City, Utah.
- Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom.
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.
- Department of Community Medicine and Epidemiology, Lady Davis Carmel Medical Center, Haifa, Israel.
- Department of Nutritional Sciences, University of Michigan School of Public Health, Ann Arbor, Michigan.
- Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio.
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio.
- Department of Medicine and Epidemiology, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.
- Department of Internal Medicine, University of Utah, Salt Lake City, Utah.
- SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington.
- Division of Laboratory Genetics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands.
- Department of Molecular Biology of Cancer, Institute of Experimental Medicine of the Czech Academy of Sciences, Prague, Czech Republic.
- Memorial University of Newfoundland, Discipline of Genetics, St. John's, Canada.
BACKGROUND: Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer.
METHODS: Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models.
RESULTS: For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif.
CONCLUSIONS: Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region.
IMPACT: The study identifies multifaceted evidence of a possible functional effect for rs1318920.
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